Cardiovascular disease is a leading cause of death in industrialized countries. Interventional surgical procedures, such as autogenous bypass operations and coronary angioplasty, often fail due to restenosis, a pathological condition wherein rapid re-occlusion of blood vessels at sites of vascular injury is elicited by manipulations performed during surgery. Restenosis arises due to the onset and maintenance of intimal hyperplasia, a process characterized by excessive cellular proliferation of vascular smooth muscle cells (VSMCs). Vascular injury caused by surgical procedures induces biological responses that stimulate VSMCs to migrate to the intima of an injured blood vessel. Intimal hyperplasia, characterized by the subsequent proliferation of VSMCs at the intima, leads to deposition of excessive extracellular matrix and ultimately, vascular occlusion.
To enhance the efficacy of vascular reconstructive procedures and prevent vein graft and arterial graft failure, it will be necessary to develop therapies for inhibiting migration and/or proliferation of VSMCs at sites of vascular injury. Drugs with anti-proliferative properties, such as rapamycin and paclitaxel, have shown promise in inhibiting VSMC migration and proliferation during clinical trials. (see, e.g., Boehm, M. and Nabel, E. G. (2003) Progress in Cell Cycle Research 5:19-30). Presently, there is an urgent need to identify and develop additional agents that are capable of reducing VSMC hyperplasia. Such agents could be applied to the prevention and treatment of restenosis and other vascular proliferative diseases.